RNA processing and its regulation: global insights into biological networks

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Abstract
The limited differences between the genomes of very different species have led to the emerging recognition that biological diversity is likely to largely derive from the complexity of RNA. This is evident in the diverse ways that RNA molecules are generated and processed and the various ways in which mRNA expression is regulated. Just as new methodologies drove a revolution in our understanding of the role of RNA in biology in the twentieth century, new high-throughput sequencing, bioinformatics and biochemical methods are now being applied to whole tissues and genetically defined systems to generate new insights into the role of RNA in biological systems. Alternative splicing is one of the best-studied mechanisms by which RNA diversity is generated. Regulation of splicing allows a means of generating RNA variants that offer great biological variability. Alternative polyadenylation is emerging as an important means for regulating 3′ UTRs, which in turn offer various means of regulating gene expression, including microRNA-mediated control of translation, RNA localization and turnover. The regulation of RNA processing involves a host of regulatory RNA-binding proteins (RNABPs) that act according to their affinities for different RNA sequences and the local abundances of RNAs and proteins. Therefore, a combination of biochemistry and cell biology will be required to fully understand RNA regulation in mammalian cells. Genome-wide analysis of RNA–protein interactions can be rigorously approached biochemically using HITS-CLIP, and methods like next-generation sequencing offer a powerful means of quantifying RNA differences to enumerate RNA diversity. Putting the two approaches together using bioinformatic tools allows genome-wide functional RNA maps to be generated, and hence new rules of RNA regulation to be discovered. An increasing number of human diseases are being found to relate to targeting of RNABPs, either through their mutation, autoimmune targeting or sequestration by RNA expansions. Applying these same genome-wide analyses to tissues affected by human disease offers the possibility of gaining new insights into disease pathogenesis and targeted therapeutics.